The pathogenesis of psoriasis has been extensively discussed for decades. Initial research focused on a keratinocyte role in the disease; in fact, until the early 1980s, psoriasis was treated as a disease primarily of keratinocytes1,2. Early work also suggested that second messenger signaling pathways, namely cAMP, was important, but a clear source or role for cAMP was never firmly established1. Subsequently, it became apparent that the immune system, namely T-cells, play an essential role in the development of psoriasis2. These data have led to the development of numerous biological and chemical therapeutics, which have greatly improved the treatment of severe psoriasis and non-skin manifestations of psoriasis such as arthritis.
Specifically there are three modalities to treat psoriasis; topical, systemic (including antimetabolites and biologics), and phototherapy. sAC inhibitors, which can block psoriatic pathophysiology, represent a new class of psoriasis therapeutics.
Topical and systemic psoriatic therapeutics function by either blocking the immune system which is responsible for secreting activating factors that stimulate keratinocyte growth or by directly inhibiting keratinocyte turnover.
Topical therapies include corticosteroids, keratolytics, anthralin, coal tar, Vitamin D analogs, and retinoids.                For steroids (corticosteroids), typically a high potency steroid is required and is applied daily. While the exact mechanism of action of topical steroids in psoriasis is largely unknown, steroids are thought to be anti-inflammatory, immunosuppressive, and antiproliferative.        Keratolytics, such as salicylic acid, work by removing scale from the psoriatic lesion. This class of medication does not affect the underlying cause of the psoriasis so the disease will remain, but the psoriasis will be less scaly. By reducing scale, other medications are able to penetrate the plaques of psoriasis more easily allowing for greater efficacy.        Anthralin and Coal tar both appear to have anti-proliferative and anti-inflammatory properties although the exact mechanism of either is not known. They both suffer from being very messy and smelly. Anthralin turns skin and fabric purple while tar stains everything black. For these reasons, patient compliance is very low.        Vitamin D analogs were first employed when physicians noticed that patients with psoriasis and altered serum calcium levels had a resolution of their psoriasis when calcium levels were normalized. Later data found that the bioactive form of Vitamin D,1,25-dihydroxycholecalciferol, has been shown to inhibit keratinocyte proliferation and promote differentiation. This topical medication is commonly used in conjunction with topical steroids. Theoretical risks of overuse include hypercalcemia.        Retinoids mediate cell differentiation and proliferation. Retinoids, specifically tazarotene, is applied topically on a daily basis and has been demonstrated to have efficacy in psoriasis. Retinoids are contraindicated in pregnancy and can be very irritating to the skin.        
Therefore, dermatologists and patients would benefit from new topical therapies for psoriasis.
Epidermal hyperplasia can occur secondary to a number of stimuli. These stimuli can be separated into congenital genetic alterations, infectious, inflammatory, and cell-cycle/apoptotic dysregulation as seen within the spectrum of epidermolytic hyperkeratosis, human papilloma virus (HPV), psoriasis, and skin cancer, respectively. Although each of these skin diseases is induced by a varied set of stimuli, they all are defined by the proliferation of keratinocytes. Keratinocyte proliferation requires alteration in programmed differentiation along with induction of the cell cycle. Cellular differentiation and cell cycle are modulated by numerous signaling pathways, and hyperstimulation or dysregulation of these pathways represents key events leading to many diseases of epidermal hyperplasia. The cyclic adenosine monophosphate (cAMP)-signaling pathway is integral to both cellular differentiation and proliferation, and has been implicated in the pathogenesis of diseases of epidermal hyperplasia such as psoriasis1,3,4,5,6.
The signaling molecule cAMP has long been studied in the epidermis. cAMP and its effector proteins, such as protein kinase-A (PKA) and cAMP-response-element-binding protein (CREB), have known roles in the cells of the epidermis and dermis, including keratinocytes, melanocytes, eccrine ductal cells, and fibroblasts7. In many cases the initiating stimulus for these cAMP-dependent pathways are well established; for example, the melanocyte-stimulating hormone-induced cAMP pathways in melanocytes8. In other cases, the stimuli leading to cAMP signal transduction are less clear.
In the present invention the role of keratinocytes and the connection to cAMP signaling with respect to psoriasis is described. There is a newly discovered source of cAMP, called bicarbonate-responsive adenylyl cylcase (brAC) and also called soluble adenylyl cyclase (sAC). sAC is unlike the more widely studied G-protein activated, transmembrane adenylyl cyclases (tmACs). sAC is insensitive to G-proteins and instead is regulated by bicarbonate ions, calcium ions, and ATP9. Because of its regulation by ATP and bicarbonate, a byproduct of CO2, this enzyme functions as a metabolic sensor10,11. In addition, unlike tmACs, which are permanently linked to the plasma membrane, sAC is present in the nucleus, where it regulates gene expression12; the mitochondria, where it influences oxidative phosphorylation13; and on the cytoskeleton, particularly the centrioles, where it is predicted to affect the cell cycle12,14. The genetic location of human sAC at 1q2415, a psoriasis genetic locus, and its stimulation by TNF16, an integral effector in psoriasis pathogenesis.
Because cAMP has an integral role in the proliferation, differentiation, and expression of key proteins in keratinocytes, the expression and localization of sAC protein in normal human skin and diseased skin provides new methods for treating skin disorders. In the present invention it is described that sAC is upregulated in the nuclei of keratinocytes in certain hyperproliferative skin diseases, including psoriasis and squamous cell carcinoma (SCC) in situ, whereas sAC is lost from the nucleus when a malignant epithelial tumor acquires invasive properties in the dermis. Accordingly, this application provides methods of treatment of skin disorders by administering inhibitors of sAC.
The inventors and others have previously described inhibitors of sAC as well as methods to identify modulators of sAC (for small molecules see published PCT applications WO2005070419, WO2008121171, WO2008088771, and WO2006113236 and US published application US2006074084; for monoclonal antibodies see references Chen et al.9, Zippin et al.14, and Buck et al.17; for RNAi see published PCT application WO2005070419). Each reference is incorporated herein by reference in its entirety).